In spite of the large medical problem which benign prostatic hyperplasia (BPH) presents, very little is known regarding the molecular basis for this disease. By analogy to recent findings in other benign tumors, it is possible that genetic alterations are important in the development of BPH. We propose to test the hypothesis that changes in the genome are associated with BPH, and that such changes may be crucial in the pathogenesis of this disease. We will take a variety of approaches to assess genomic alterations in both human and canine BPH, focusing on both spontaneous and experimentally induced disease in the latter. The three specific questions to be addressed are as follows: 1) is the development of BPH associated with the accumulation of DNA damage in the form of altered nucleotides?; 2) do the patterns of DNA methylation change in BPH, indicating a global genomic change, predisposing to genetic instability?; and 3) can any of the genetic alterations which have been found in prostate cancer be detected in the genome of BPH cells? Of particular importance to each of these questions is how these processes are affected by aging and exposure to steroid hormones, these factors being the only known etiologic agents in this disease. These studies are of particular relevance given the recent evidence presented in this program application that 1) there may be strong similarities between the etiologic pathways for both hyperplasia and cancer int he prostate, and 2) there may be an inherited (genetic) predisposition to BPH in certain individuals. It is anticipated that the proposed studies will not only provide important insight into the molecular mechanisms responsible for BPH, but also might identify new targets for more effective therapeutic intervention in this common disease.